EA029925B1 - Способ усовершенствованного синтеза опиоидов - Google Patents

Info

Publication number

EA029925B1

EA029925B1 EA201590221A EA201590221A EA029925B1 EA 029925 B1 EA029925 B1 EA 029925B1 EA 201590221 A EA201590221 A EA 201590221A EA 201590221 A EA201590221 A EA 201590221A EA 029925 B1 EA029925 B1 EA 029925B1

Authority

EA

Eurasian Patent Office

Prior art keywords

compound

formula

ppm

acid

solvate

Prior art date

2012-07-16

Links

• Espacenet
• Global Dossier
• Discuss

• 238000000034 method Methods 0.000 title claims abstract description 213
• 230000015572 biosynthetic process Effects 0.000 title claims description 44
• 230000008569 process Effects 0.000 title abstract description 48
• 238000003786 synthesis reaction Methods 0.000 title description 5
• 150000001875 compounds Chemical class 0.000 claims abstract description 831
• 239000012453 solvate Substances 0.000 claims abstract description 464
• 150000003839 salts Chemical class 0.000 claims abstract description 343
• 239000002253 acid Substances 0.000 claims description 217
• 239000011541 reaction mixture Substances 0.000 claims description 161
• BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical group O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 claims description 110
• 229960002085 oxycodone Drugs 0.000 claims description 99
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 98
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 86
• 238000001556 precipitation Methods 0.000 claims description 67
• 238000007254 oxidation reaction Methods 0.000 claims description 64
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 62
• 150000004965 peroxy acids Chemical class 0.000 claims description 59
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 49
• 235000019253 formic acid Nutrition 0.000 claims description 49
• WQRROQFAVLFQDK-RKXJKUSZSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,7a,13-tetrahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;sulfuric acid Chemical group OS(O)(=O)=O.O=C([C@@H]1O2)C=C[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C WQRROQFAVLFQDK-RKXJKUSZSA-N 0.000 claims description 48
• 239000002244 precipitate Substances 0.000 claims description 45
• 239000007800 oxidant agent Substances 0.000 claims description 39
• 239000000725 suspension Substances 0.000 claims description 35
• FQXXSQDCDRQNQE-VMDGZTHMSA-N thebaine Chemical compound C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(OC)C5=C4[C@@]21[C@H]3O5 FQXXSQDCDRQNQE-VMDGZTHMSA-N 0.000 claims description 35
• FQXXSQDCDRQNQE-UHFFFAOYSA-N (-)-thebaine Chemical compound COC1=CC=C2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 FQXXSQDCDRQNQE-UHFFFAOYSA-N 0.000 claims description 28
• 229930003945 thebaine Natural products 0.000 claims description 23
• 125000000217 alkyl group Chemical group 0.000 claims description 20
• 230000001376 precipitating effect Effects 0.000 claims description 14
• 230000001590 oxidative effect Effects 0.000 claims description 13
• LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical compound NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 11
• KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 11
• 238000002955 isolation Methods 0.000 claims description 10
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 8
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
• 229910052700 potassium Inorganic materials 0.000 claims description 5
• 239000011591 potassium Substances 0.000 claims description 5
• XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 claims description 2
• 229910052921 ammonium sulfate Inorganic materials 0.000 claims 1
• 230000002085 persistent effect Effects 0.000 claims 1
• 239000002552 dosage form Substances 0.000 abstract description 93
• 238000004519 manufacturing process Methods 0.000 abstract description 35
• 239000008186 active pharmaceutical agent Substances 0.000 abstract description 27
• 229940005483 opioid analgesics Drugs 0.000 abstract description 20
• 238000002360 preparation method Methods 0.000 abstract description 18
• 235000002639 sodium chloride Nutrition 0.000 description 340
• 239000000203 mixture Substances 0.000 description 285
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 125
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 109
• 229910001868 water Inorganic materials 0.000 description 107
• 238000004128 high performance liquid chromatography Methods 0.000 description 95
• 238000006243 chemical reaction Methods 0.000 description 76
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 73
• 239000000243 solution Substances 0.000 description 73
• YYCRAERBSFHMPL-XFKAJCMBSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,7a,13-tetrahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical compound O=C([C@@H]1O2)C=C[C@@]3(O)[C@]4([H])N(C)CC[C@]13C1=C2C(OC)=CC=C1C4 YYCRAERBSFHMPL-XFKAJCMBSA-N 0.000 description 68
• 239000000126 substance Substances 0.000 description 67
• 239000002904 solvent Substances 0.000 description 66
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 66
• 239000007787 solid Substances 0.000 description 65
• YYCRAERBSFHMPL-UHFFFAOYSA-N 14beta-Hydroxycodeinone Natural products O1C2C(=O)C=CC3(O)C4CC5=CC=C(OC)C1=C5C23CCN4C YYCRAERBSFHMPL-UHFFFAOYSA-N 0.000 description 63
• -1 1-methylpentyl Chemical group 0.000 description 56
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 54
• 238000013268 sustained release Methods 0.000 description 52
• 239000012730 sustained-release form Substances 0.000 description 52
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 51
• RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 51
• 239000000047 product Substances 0.000 description 50
• 239000008194 pharmaceutical composition Substances 0.000 description 49
• 230000002209 hydrophobic effect Effects 0.000 description 46
• 238000000576 coating method Methods 0.000 description 44
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
• 235000019441 ethanol Nutrition 0.000 description 42
• ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical compound COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 description 38
• 238000005984 hydrogenation reaction Methods 0.000 description 38
• 239000012296 anti-solvent Substances 0.000 description 34
• 229960003617 oxycodone hydrochloride Drugs 0.000 description 34
• BQNSLJQRJAJITR-UHFFFAOYSA-N 1,1,2-trichloro-1,2-difluoroethane Chemical compound FC(Cl)C(F)(Cl)Cl BQNSLJQRJAJITR-UHFFFAOYSA-N 0.000 description 33
• 239000011248 coating agent Substances 0.000 description 31
• 229940079593 drug Drugs 0.000 description 30
• 239000003814 drug Substances 0.000 description 30
• SVFULCKGJOWFGT-UQIOWFBZSA-N COc1ccc2C[C@H]3N(C)CC[C@@]45[C@@H](Oc1c24)C(=O)CC(O)[C@@]35O Chemical compound COc1ccc2C[C@H]3N(C)CC[C@@]45[C@@H](Oc1c24)C(=O)CC(O)[C@@]35O SVFULCKGJOWFGT-UQIOWFBZSA-N 0.000 description 29
• 239000002585 base Substances 0.000 description 28
• 229960004592 isopropanol Drugs 0.000 description 27
• 239000002245 particle Substances 0.000 description 27
• SVFULCKGJOWFGT-XZFSWKSHSA-N (4r,4as,5r,7ar,12bs)-4a,5-dihydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical compound O=C([C@@H]1O2)C[C@@H](O)[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C SVFULCKGJOWFGT-XZFSWKSHSA-N 0.000 description 26
• 230000003647 oxidation Effects 0.000 description 25
• 238000006722 reduction reaction Methods 0.000 description 25
• 229920000642 polymer Polymers 0.000 description 24
• 239000000543 intermediate Substances 0.000 description 23
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 22
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
• 239000008187 granular material Substances 0.000 description 22
• 239000011159 matrix material Substances 0.000 description 21
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
• 150000001450 anions Chemical class 0.000 description 20
• 239000004014 plasticizer Substances 0.000 description 20
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 19
• 239000003054 catalyst Substances 0.000 description 19
• 239000003795 chemical substances by application Substances 0.000 description 19
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 18
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
• 239000008367 deionised water Substances 0.000 description 18
• 229910021641 deionized water Inorganic materials 0.000 description 18
• 239000007858 starting material Substances 0.000 description 18
• 238000002425 crystallisation Methods 0.000 description 17
• 230000008025 crystallization Effects 0.000 description 17
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 16
• 239000006186 oral dosage form Substances 0.000 description 16
• MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 15
• 239000006227 byproduct Substances 0.000 description 15
• 239000006185 dispersion Substances 0.000 description 15
• 238000009472 formulation Methods 0.000 description 15
• 229920000058 polyacrylate Polymers 0.000 description 15
• 239000000829 suppository Substances 0.000 description 15
• FJNCXZZQNBKEJT-UHFFFAOYSA-N 8beta-hydroxymarrubiin Natural products O1C(=O)C2(C)CCCC3(C)C2C1CC(C)(O)C3(O)CCC=1C=COC=1 FJNCXZZQNBKEJT-UHFFFAOYSA-N 0.000 description 14
• 229920001577 copolymer Polymers 0.000 description 14
• 239000000706 filtrate Substances 0.000 description 14
• 239000000463 material Substances 0.000 description 14
• BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical group O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 14
• BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 14
• 229940099371 diacetylated monoglycerides Drugs 0.000 description 13
• 239000012530 fluid Substances 0.000 description 13
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 12
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• LLRZWSLBLGNDFM-XFKAJCMBSA-N [(4R,4aS,7aR,12bS)-9-methoxy-3-methyl-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-4a-yl] hydrogen sulfate Chemical compound S(=O)(=O)(O)O[C@@]12CCC([C@H]3[C@]11C=4C(=C(C=CC=4C[C@H]2N(C)CC1)OC)O3)=O LLRZWSLBLGNDFM-XFKAJCMBSA-N 0.000 description 12
• BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 12
• 239000013078 crystal Substances 0.000 description 12
• 230000008021 deposition Effects 0.000 description 12
• NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 12
• 239000012634 fragment Substances 0.000 description 12
• ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 12
• 150000004682 monohydrates Chemical class 0.000 description 12
• 229920003171 Poly (ethylene oxide) Polymers 0.000 description 11
• 229920013820 alkyl cellulose Polymers 0.000 description 11
• 229910052763 palladium Inorganic materials 0.000 description 11
• 238000003756 stirring Methods 0.000 description 11
• 238000005406 washing Methods 0.000 description 11
• 239000001993 wax Substances 0.000 description 11
• 239000001856 Ethyl cellulose Substances 0.000 description 10
• ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 10
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
• DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 10
• 239000011230 binding agent Substances 0.000 description 10
• 125000004432 carbon atom Chemical group C* 0.000 description 10
• 150000001768 cations Chemical group 0.000 description 10
• 229920001249 ethyl cellulose Polymers 0.000 description 10
• 235000019325 ethyl cellulose Nutrition 0.000 description 10
• 239000012458 free base Substances 0.000 description 10
• 229920013821 hydroxy alkyl cellulose Polymers 0.000 description 10
• 230000003204 osmotic effect Effects 0.000 description 10
• 229920001515 polyalkylene glycol Polymers 0.000 description 10
• 230000002829 reductive effect Effects 0.000 description 10
• 239000003826 tablet Substances 0.000 description 10
• DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 9
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• 150000007513 acids Chemical class 0.000 description 9
• NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 9
• 229910052799 carbon Inorganic materials 0.000 description 9
• 239000007795 chemical reaction product Substances 0.000 description 9
• 235000014113 dietary fatty acids Nutrition 0.000 description 9
• 239000000975 dye Substances 0.000 description 9
• 239000000194 fatty acid Substances 0.000 description 9
• 229930195729 fatty acid Natural products 0.000 description 9
• 239000004615 ingredient Substances 0.000 description 9
• 229940098779 methanesulfonic acid Drugs 0.000 description 9
• 230000009467 reduction Effects 0.000 description 9
• 239000002511 suppository base Substances 0.000 description 9
• SVFULCKGJOWFGT-FGPFUNDFSA-N (4r,4as,5s,7ar,12bs)-4a,5-dihydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical compound O=C([C@@H]1O2)C[C@H](O)[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C SVFULCKGJOWFGT-FGPFUNDFSA-N 0.000 description 8
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
• ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 8
• 230000002378 acidificating effect Effects 0.000 description 8
• 239000013543 active substance Substances 0.000 description 8
• 238000004458 analytical method Methods 0.000 description 8
• 229920002678 cellulose Polymers 0.000 description 8
• 239000003153 chemical reaction reagent Substances 0.000 description 8
• 238000001816 cooling Methods 0.000 description 8
• 230000000694 effects Effects 0.000 description 8
• 150000002148 esters Chemical class 0.000 description 8
• 150000004687 hexahydrates Chemical class 0.000 description 8
• 239000007788 liquid Substances 0.000 description 8
• 239000000155 melt Substances 0.000 description 8
• GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 8
• 230000036407 pain Effects 0.000 description 8
• 150000004686 pentahydrates Chemical class 0.000 description 8
• 238000012545 processing Methods 0.000 description 8
• 230000001105 regulatory effect Effects 0.000 description 8
• 239000000758 substrate Substances 0.000 description 8
• UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 description 7
• 229920002125 Sokalan® Polymers 0.000 description 7
• 239000000654 additive Substances 0.000 description 7
• 150000001298 alcohols Chemical class 0.000 description 7
• 150000004665 fatty acids Chemical class 0.000 description 7
• OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 7
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
• 229960005181 morphine Drugs 0.000 description 7
• 229960005118 oxymorphone Drugs 0.000 description 7
• 239000000546 pharmaceutical excipient Substances 0.000 description 7
• 239000004584 polyacrylic acid Substances 0.000 description 7
• 239000002243 precursor Substances 0.000 description 7
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
• 206010011224 Cough Diseases 0.000 description 6
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
• GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 6
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
• 238000010521 absorption reaction Methods 0.000 description 6
• 230000000996 additive effect Effects 0.000 description 6
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
• WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 6
• 239000001913 cellulose Substances 0.000 description 6
• 239000011162 core material Substances 0.000 description 6
• 238000010586 diagram Methods 0.000 description 6
• 230000002496 gastric effect Effects 0.000 description 6
• 239000008240 homogeneous mixture Substances 0.000 description 6
• 229930195733 hydrocarbon Natural products 0.000 description 6
• 150000002430 hydrocarbons Chemical class 0.000 description 6
• 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 6
• 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 6
• 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 6
• UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 6
• 239000000314 lubricant Substances 0.000 description 6
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
• 239000002609 medium Substances 0.000 description 6
• 229920003145 methacrylic acid copolymer Polymers 0.000 description 6
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
• 229910052757 nitrogen Inorganic materials 0.000 description 6
• VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 6
• 150000002978 peroxides Chemical class 0.000 description 6
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 5
• ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 5
• 229940093475 2-ethoxyethanol Drugs 0.000 description 5
• FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 5
• 206010012335 Dependence Diseases 0.000 description 5
• 229920002845 Poly(methacrylic acid) Polymers 0.000 description 5
• DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 5
• 239000007864 aqueous solution Substances 0.000 description 5
• 239000002775 capsule Substances 0.000 description 5
• 235000010980 cellulose Nutrition 0.000 description 5
• 229920002301 cellulose acetate Polymers 0.000 description 5
• 229960004126 codeine Drugs 0.000 description 5
• 125000000753 cycloalkyl group Chemical group 0.000 description 5
• 230000001419 dependent effect Effects 0.000 description 5
• XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 5
• 238000001125 extrusion Methods 0.000 description 5
• 239000000796 flavoring agent Substances 0.000 description 5
• 239000007903 gelatin capsule Substances 0.000 description 5
• 238000002844 melting Methods 0.000 description 5
• 230000008018 melting Effects 0.000 description 5
• 239000012452 mother liquor Substances 0.000 description 5
• 231100000252 nontoxic Toxicity 0.000 description 5
• 230000003000 nontoxic effect Effects 0.000 description 5
• 239000000049 pigment Substances 0.000 description 5
• 229920001223 polyethylene glycol Polymers 0.000 description 5
• 150000003467 sulfuric acid derivatives Chemical class 0.000 description 5
• 208000011580 syndromic disease Diseases 0.000 description 5
• 239000001069 triethyl citrate Substances 0.000 description 5
• VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 5
• 235000013769 triethyl citrate Nutrition 0.000 description 5
• OMZZEHGIDAJPCT-XFKAJCMBSA-N (4R,4aS,7aR,12bS)-4a,11-dihydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one Chemical compound COc1cc(O)c2C[C@H]3N(C)CC[C@@]45[C@@H](Oc1c24)C(=O)CC[C@@]35O OMZZEHGIDAJPCT-XFKAJCMBSA-N 0.000 description 4
• WRRSFOZOETZUPG-FFHNEAJVSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;hydrate Chemical compound O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC WRRSFOZOETZUPG-FFHNEAJVSA-N 0.000 description 4
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
• ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
• JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
• 239000002841 Lewis acid Substances 0.000 description 4
• HLMSIZPQBSYUNL-IPOQPSJVSA-N Noroxymorphone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4 HLMSIZPQBSYUNL-IPOQPSJVSA-N 0.000 description 4
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
• 229920002472 Starch Polymers 0.000 description 4
• ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 description 4
• 239000000908 ammonium hydroxide Substances 0.000 description 4
• OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Natural products C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 4
• 239000003086 colorant Substances 0.000 description 4
• 238000007796 conventional method Methods 0.000 description 4
• FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 4
• 150000004683 dihydrates Chemical class 0.000 description 4
• 239000003085 diluting agent Substances 0.000 description 4
• 238000004090 dissolution Methods 0.000 description 4
• 150000002191 fatty alcohols Chemical class 0.000 description 4
• 239000000945 filler Substances 0.000 description 4
• 238000001914 filtration Methods 0.000 description 4
• 239000000017 hydrogel Substances 0.000 description 4
• 239000001257 hydrogen Substances 0.000 description 4
• 229910052739 hydrogen Inorganic materials 0.000 description 4
• 239000012729 immediate-release (IR) formulation Substances 0.000 description 4
• 150000002576 ketones Chemical class 0.000 description 4
• 150000007517 lewis acids Chemical class 0.000 description 4
• 229910052751 metal Inorganic materials 0.000 description 4
• 239000002184 metal Substances 0.000 description 4
• 125000005395 methacrylic acid group Chemical class 0.000 description 4
• RGPDIGOSVORSAK-STHHAXOLSA-N naloxone hydrochloride Chemical compound Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C RGPDIGOSVORSAK-STHHAXOLSA-N 0.000 description 4
• 230000035699 permeability Effects 0.000 description 4
• 229920000233 poly(alkylene oxides) Polymers 0.000 description 4
• 229920001451 polypropylene glycol Polymers 0.000 description 4
• 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
• 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
• 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
• 239000011148 porous material Substances 0.000 description 4
• 230000005588 protonation Effects 0.000 description 4
• 239000008107 starch Substances 0.000 description 4
• 235000019698 starch Nutrition 0.000 description 4
• 210000002784 stomach Anatomy 0.000 description 4
• 150000004685 tetrahydrates Chemical class 0.000 description 4
• 238000012546 transfer Methods 0.000 description 4
• 230000009466 transformation Effects 0.000 description 4
• URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
• 150000003626 triacylglycerols Chemical class 0.000 description 4
• 150000004684 trihydrates Chemical class 0.000 description 4
• 239000008096 xylene Substances 0.000 description 4
• LHTAJTFGGUDLRH-QMVVXIJUSA-N (4r,4as,7s,7ar,12bs)-9-methoxy-3-methyl-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diol Chemical compound O[C@H]([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C LHTAJTFGGUDLRH-QMVVXIJUSA-N 0.000 description 3
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
• 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 3
• 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
• 229910015900 BF3 Inorganic materials 0.000 description 3
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
• 239000004215 Carbon black (E152) Substances 0.000 description 3
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
• 108010010803 Gelatin Proteins 0.000 description 3
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
• 239000002202 Polyethylene glycol Substances 0.000 description 3
• 229920001800 Shellac Polymers 0.000 description 3
• 235000021355 Stearic acid Nutrition 0.000 description 3
• 229920002494 Zein Polymers 0.000 description 3
• 125000003158 alcohol group Chemical group 0.000 description 3
• 150000001408 amides Chemical class 0.000 description 3
• 125000004429 atom Chemical group 0.000 description 3
• 229920003086 cellulose ether Polymers 0.000 description 3
• 230000007423 decrease Effects 0.000 description 3
• 239000003937 drug carrier Substances 0.000 description 3
• 230000002708 enhancing effect Effects 0.000 description 3
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
• 235000013355 food flavoring agent Nutrition 0.000 description 3
• 229920000159 gelatin Polymers 0.000 description 3
• 239000008273 gelatin Substances 0.000 description 3
• 235000019322 gelatine Nutrition 0.000 description 3
• 235000011852 gelatine desserts Nutrition 0.000 description 3
• 239000003979 granulating agent Substances 0.000 description 3
• 238000010438 heat treatment Methods 0.000 description 3
• LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 3
• 229960000240 hydrocodone Drugs 0.000 description 3
• 150000002440 hydroxy compounds Chemical class 0.000 description 3
• 230000001965 increasing effect Effects 0.000 description 3
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
• JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
• 229940011051 isopropyl acetate Drugs 0.000 description 3
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
• GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 3
• 239000008101 lactose Substances 0.000 description 3
• 235000019359 magnesium stearate Nutrition 0.000 description 3
• 238000007909 melt granulation Methods 0.000 description 3
• 125000005397 methacrylic acid ester group Chemical group 0.000 description 3
• GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 3
• 229960004127 naloxone Drugs 0.000 description 3
• 230000007935 neutral effect Effects 0.000 description 3
• QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
• OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
• 229940051877 other opioids in atc Drugs 0.000 description 3
• 235000006408 oxalic acid Nutrition 0.000 description 3
• FWFGVMYFCODZRD-UHFFFAOYSA-N oxidanium;hydrogen sulfate Chemical compound O.OS(O)(=O)=O FWFGVMYFCODZRD-UHFFFAOYSA-N 0.000 description 3
• 230000037361 pathway Effects 0.000 description 3
• 230000000704 physical effect Effects 0.000 description 3
• 239000000843 powder Substances 0.000 description 3
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
• 239000003223 protective agent Substances 0.000 description 3
• 125000001453 quaternary ammonium group Chemical group 0.000 description 3
• 239000000376 reactant Substances 0.000 description 3
• 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
• 235000013874 shellac Nutrition 0.000 description 3
• ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 3
• 239000004208 shellac Substances 0.000 description 3
• 229940113147 shellac Drugs 0.000 description 3
• 238000005507 spraying Methods 0.000 description 3
• 239000008117 stearic acid Substances 0.000 description 3
• 239000006228 supernatant Substances 0.000 description 3
• 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
• 239000004408 titanium dioxide Substances 0.000 description 3
• 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 3
• LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 3
• 238000009901 transfer hydrogenation reaction Methods 0.000 description 3
• 229920002554 vinyl polymer Polymers 0.000 description 3
• 239000005019 zein Substances 0.000 description 3
• 229940093612 zein Drugs 0.000 description 3
• RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical class Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 description 2
• QUCDIPJOMHOACP-RUPCJGSHSA-N (4R,4aS,5R,7aR,12bS)-4a,5-dihydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one hydrochloride Chemical compound Cl.COc1ccc2C[C@H]3N(C)CC[C@@]45[C@@H](Oc1c24)C(=O)C[C@@H](O)[C@@]35O QUCDIPJOMHOACP-RUPCJGSHSA-N 0.000 description 2
• SXHURKJPBYEAQN-NFEUPGRZSA-N (4R,4aS,7aR,12bS)-4a,13-dihydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one Chemical compound COc1ccc2C(O)[C@H]3N(C)CC[C@@]45[C@@H](Oc1c24)C(=O)CC[C@@]35O SXHURKJPBYEAQN-NFEUPGRZSA-N 0.000 description 2
• CCAANTXTVVWGAR-RKXJKUSZSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;2,2,2-trifluoroacetic acid Chemical group OC(=O)C(F)(F)F.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C CCAANTXTVVWGAR-RKXJKUSZSA-N 0.000 description 2
• UHOSPHRLTGJLBB-RKXJKUSZSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,7a,13-tetrahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;hydrochloride Chemical compound Cl.O=C([C@@H]1O2)C=C[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C UHOSPHRLTGJLBB-RKXJKUSZSA-N 0.000 description 2
• GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
• LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
• 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 2
• 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 2
• OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
• YPZPXTZKBNWUTF-UHFFFAOYSA-N 14beta-Hydroxy-codein Natural products O1C2C(O)C=CC3(O)C4CC5=CC=C(OC)C1=C5C23CCN4C YPZPXTZKBNWUTF-UHFFFAOYSA-N 0.000 description 2
• ARGCQEVBJHPOGB-UHFFFAOYSA-N 2,5-dihydrofuran Chemical compound C1OCC=C1 ARGCQEVBJHPOGB-UHFFFAOYSA-N 0.000 description 2
• SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 2
• SFPNZPQIIAJXGL-UHFFFAOYSA-N 2-ethoxyethyl 2-methylprop-2-enoate Chemical class CCOCCOC(=O)C(C)=C SFPNZPQIIAJXGL-UHFFFAOYSA-N 0.000 description 2
• 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 2
• 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
• 125000005916 2-methylpentyl group Chemical group 0.000 description 2
• LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
• 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
• 125000005917 3-methylpentyl group Chemical group 0.000 description 2
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
• 244000215068 Acacia senegal Species 0.000 description 2
• CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
• KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
• 239000007848 Bronsted acid Substances 0.000 description 2
• 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
• 229920001747 Cellulose diacetate Polymers 0.000 description 2
• 229920002284 Cellulose triacetate Polymers 0.000 description 2
• 206010010774 Constipation Diseases 0.000 description 2
• 208000020401 Depressive disease Diseases 0.000 description 2
• 206010012735 Diarrhoea Diseases 0.000 description 2
• MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
• 241000196324 Embryophyta Species 0.000 description 2
• 229930091371 Fructose Natural products 0.000 description 2
• 239000005715 Fructose Substances 0.000 description 2
• RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
• 229920000084 Gum arabic Polymers 0.000 description 2
• 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
• UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
• 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
• GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
• 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
• RIKMCJUNPCRFMW-ISWURRPUSA-N Noroxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4 RIKMCJUNPCRFMW-ISWURRPUSA-N 0.000 description 2
• CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
• 102000003840 Opioid Receptors Human genes 0.000 description 2
• 108090000137 Opioid Receptors Proteins 0.000 description 2
• 229910019142 PO4 Inorganic materials 0.000 description 2
• 239000004952 Polyamide Substances 0.000 description 2
• 239000004793 Polystyrene Substances 0.000 description 2
• WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
• XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
• ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
• 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 2
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
• WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
• NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 description 2
• 235000010489 acacia gum Nutrition 0.000 description 2
• 239000000205 acacia gum Substances 0.000 description 2
• KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
• 238000013019 agitation Methods 0.000 description 2
• 229910052783 alkali metal Inorganic materials 0.000 description 2
• 125000003342 alkenyl group Chemical group 0.000 description 2
• 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
• 150000001449 anionic compounds Chemical class 0.000 description 2
• 239000005557 antagonist Substances 0.000 description 2
• 239000003963 antioxidant agent Substances 0.000 description 2
• 235000006708 antioxidants Nutrition 0.000 description 2
• OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 2
• 235000013871 bee wax Nutrition 0.000 description 2
• 239000012166 beeswax Substances 0.000 description 2
• GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 2
• CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
• CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
• 150000001720 carbohydrates Chemical class 0.000 description 2
• 235000014633 carbohydrates Nutrition 0.000 description 2
• 239000004203 carnauba wax Substances 0.000 description 2
• 235000013869 carnauba wax Nutrition 0.000 description 2
• 239000004359 castor oil Substances 0.000 description 2
• 235000019438 castor oil Nutrition 0.000 description 2
• 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
• 229940082500 cetostearyl alcohol Drugs 0.000 description 2
• 230000008859 change Effects 0.000 description 2
• 239000007810 chemical reaction solvent Substances 0.000 description 2
• XYYVYLMBEZUESM-CMKMFDCUSA-N codeinone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=CC(=O)[C@@H]1OC1=C2C3=CC=C1OC XYYVYLMBEZUESM-CMKMFDCUSA-N 0.000 description 2
• 238000013270 controlled release Methods 0.000 description 2
• 230000001276 controlling effect Effects 0.000 description 2
• HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
• 230000003111 delayed effect Effects 0.000 description 2
• DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
• 238000009505 enteric coating Methods 0.000 description 2
• 239000002702 enteric coating Substances 0.000 description 2
• VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 2
• 239000012467 final product Substances 0.000 description 2
• 235000019634 flavors Nutrition 0.000 description 2
• QEWYKACRFQMRMB-UHFFFAOYSA-M fluoroacetate Chemical compound [O-]C(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-M 0.000 description 2
• 210000001035 gastrointestinal tract Anatomy 0.000 description 2
• ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
• 239000001087 glyceryl triacetate Substances 0.000 description 2
• 235000013773 glyceryl triacetate Nutrition 0.000 description 2
• BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
• 150000002431 hydrogen Chemical class 0.000 description 2
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
• 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
• 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
• 230000006872 improvement Effects 0.000 description 2
• 230000000977 initiatory effect Effects 0.000 description 2
• 206010022437 insomnia Diseases 0.000 description 2
• 230000000968 intestinal effect Effects 0.000 description 2
• 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 2
• 239000004922 lacquer Substances 0.000 description 2
• 238000002386 leaching Methods 0.000 description 2
• 150000002632 lipids Chemical class 0.000 description 2
• KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
• 239000007937 lozenge Substances 0.000 description 2
• 229940117841 methacrylic acid copolymer Drugs 0.000 description 2
• 229940016286 microcrystalline cellulose Drugs 0.000 description 2
• 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
• 239000008108 microcrystalline cellulose Substances 0.000 description 2
• 238000002156 mixing Methods 0.000 description 2
• 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
• WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
• 150000002891 organic anions Chemical class 0.000 description 2
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
• 239000008188 pellet Substances 0.000 description 2
• VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 2
• JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 2
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
• 229920003229 poly(methyl methacrylate) Polymers 0.000 description 2
• 229920002647 polyamide Polymers 0.000 description 2
• 229920000193 polymethacrylate Polymers 0.000 description 2
• 239000004926 polymethyl methacrylate Substances 0.000 description 2
• 229920002223 polystyrene Polymers 0.000 description 2
• 239000000651 prodrug Substances 0.000 description 2
• 229940002612 prodrug Drugs 0.000 description 2
• 235000013772 propylene glycol Nutrition 0.000 description 2
• 238000000746 purification Methods 0.000 description 2
• 230000035484 reaction time Effects 0.000 description 2
• 238000001953 recrystallisation Methods 0.000 description 2
• 238000010992 reflux Methods 0.000 description 2
• 238000004007 reversed phase HPLC Methods 0.000 description 2
• 239000013049 sediment Substances 0.000 description 2
• 210000000813 small intestine Anatomy 0.000 description 2
• 239000011734 sodium Substances 0.000 description 2
• 229910052708 sodium Inorganic materials 0.000 description 2
• 229940083542 sodium Drugs 0.000 description 2
• 239000000454 talc Substances 0.000 description 2
• 229910052623 talc Inorganic materials 0.000 description 2
• 235000012222 talc Nutrition 0.000 description 2
• PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 description 2
• HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
• OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 2
• 229920001169 thermoplastic Polymers 0.000 description 2
• 239000004416 thermosoftening plastic Substances 0.000 description 2
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
• 239000006211 transdermal dosage form Substances 0.000 description 2
• 229960002622 triacetin Drugs 0.000 description 2
• LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
• 229910052720 vanadium Inorganic materials 0.000 description 2
• 239000002966 varnish Substances 0.000 description 2
• 235000015112 vegetable and seed oil Nutrition 0.000 description 2
• 239000008158 vegetable oil Substances 0.000 description 2
• 229920003169 water-soluble polymer Polymers 0.000 description 2
• 150000003738 xylenes Chemical class 0.000 description 2
• GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
• JVLBPIPGETUEET-WIXLDOGYSA-O (3r,4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one Chemical compound C([N@+]1(C)[C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)C1CC1 JVLBPIPGETUEET-WIXLDOGYSA-O 0.000 description 1
• YTLQUSFUTUNUQM-KFIKYVJASA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;(4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,7a,13-tetrahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C.O=C([C@@H]1O2)C=C[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C YTLQUSFUTUNUQM-KFIKYVJASA-N 0.000 description 1
• AQWNHBRZCAXZQM-KDKWOIFOSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;hydrochloride Chemical compound Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C AQWNHBRZCAXZQM-KDKWOIFOSA-N 0.000 description 1
• UEVFEOWRBXXYNU-KDKWOIFOSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,7a,13-tetrahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;sulfuric acid Chemical compound OS(O)(=O)=O.O=C([C@@H]1O2)C=C[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C.O=C([C@@H]1O2)C=C[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C UEVFEOWRBXXYNU-KDKWOIFOSA-N 0.000 description 1
• IGUAHHYADOOLFE-PCHTVJFHSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,7a,13-tetrahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;sulfuric acid;hydrate Chemical compound O.OS(O)(=O)=O.O=C([C@@H]1O2)C=C[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C IGUAHHYADOOLFE-PCHTVJFHSA-N 0.000 description 1
• MPJXSJWIZLPBSG-RKXJKUSZSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,7a,13-tetrahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;trifluoromethanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)F.O=C([C@@H]1O2)C=C[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C MPJXSJWIZLPBSG-RKXJKUSZSA-N 0.000 description 1
• GXMDLXQESSRSFB-ZWKGOLINSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-3-oxido-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one Chemical compound C([C@@]1(O)[C@H]([N+](CC[C@@]112)(C)[O-])C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC GXMDLXQESSRSFB-ZWKGOLINSA-N 0.000 description 1
• WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
• ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
• WCOXQTXVACYMLM-UHFFFAOYSA-N 2,3-bis(12-hydroxyoctadecanoyloxy)propyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC(O)CCCCCC)COC(=O)CCCCCCCCCCC(O)CCCCCC WCOXQTXVACYMLM-UHFFFAOYSA-N 0.000 description 1
• CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
• WLQMYDWPKCQDPQ-UHFFFAOYSA-N 2,6-ditert-butyl-4-chlorophenol Chemical compound CC(C)(C)C1=CC(Cl)=CC(C(C)(C)C)=C1O WLQMYDWPKCQDPQ-UHFFFAOYSA-N 0.000 description 1
• SJIXRGNQPBQWMK-UHFFFAOYSA-N 2-(diethylamino)ethyl 2-methylprop-2-enoate Chemical compound CCN(CC)CCOC(=O)C(C)=C SJIXRGNQPBQWMK-UHFFFAOYSA-N 0.000 description 1
• VKNASXZDGZNEDA-UHFFFAOYSA-N 2-cyanoethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCC#N VKNASXZDGZNEDA-UHFFFAOYSA-N 0.000 description 1
• WROUWQQRXUBECT-UHFFFAOYSA-N 2-ethylacrylic acid Chemical compound CCC(=C)C(O)=O WROUWQQRXUBECT-UHFFFAOYSA-N 0.000 description 1
• BXVSAYBZSGIURM-UHFFFAOYSA-N 2-phenoxy-4h-1,3,2$l^{5}-benzodioxaphosphinine 2-oxide Chemical compound O1CC2=CC=CC=C2OP1(=O)OC1=CC=CC=C1 BXVSAYBZSGIURM-UHFFFAOYSA-N 0.000 description 1
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
• LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
• MRBKEAMVRSLQPH-UHFFFAOYSA-N 3-tert-butyl-4-hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1 MRBKEAMVRSLQPH-UHFFFAOYSA-N 0.000 description 1
• KBIWNQVZKHSHTI-UHFFFAOYSA-N 4-n,4-n-dimethylbenzene-1,4-diamine;oxalic acid Chemical compound OC(=O)C(O)=O.CN(C)C1=CC=C(N)C=C1 KBIWNQVZKHSHTI-UHFFFAOYSA-N 0.000 description 1
• KWSLGOVYXMQPPX-UHFFFAOYSA-N 5-[3-(trifluoromethyl)phenyl]-2h-tetrazole Chemical compound FC(F)(F)C1=CC=CC(C2=NNN=N2)=C1 KWSLGOVYXMQPPX-UHFFFAOYSA-N 0.000 description 1
• FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
• QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
• 229920002126 Acrylic acid copolymer Polymers 0.000 description 1
• 229920000178 Acrylic resin Polymers 0.000 description 1
• 239000004925 Acrylic resin Substances 0.000 description 1
• 229920000856 Amylose Polymers 0.000 description 1
• 239000004604 Blowing Agent Substances 0.000 description 1
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
• 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
• 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
• NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
• 101100283604 Caenorhabditis elegans pigk-1 gene Proteins 0.000 description 1
• 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
• 229920001661 Chitosan Polymers 0.000 description 1
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
• KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
• 229920002261 Corn starch Polymers 0.000 description 1
• FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
• FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
• PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 1
• 101100520660 Drosophila melanogaster Poc1 gene Proteins 0.000 description 1
• VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
• IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 1
• JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
• 239000005977 Ethylene Substances 0.000 description 1
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
• 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
• 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
• 235000000177 Indigofera tinctoria Nutrition 0.000 description 1
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
• QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
• 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
• FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
• JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
• 239000002879 Lewis base Substances 0.000 description 1
• 240000006240 Linum usitatissimum Species 0.000 description 1
• 235000004431 Linum usitatissimum Nutrition 0.000 description 1
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
• 239000005913 Maltodextrin Substances 0.000 description 1
• 229920002774 Maltodextrin Polymers 0.000 description 1
• 241000124008 Mammalia Species 0.000 description 1
• 241001465754 Metazoa Species 0.000 description 1
• CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
• CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
• SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
• 229910002651 NO3 Inorganic materials 0.000 description 1
• WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 description 1
• NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
• DXIRRDROGPMTPD-XFKAJCMBSA-N OO[C@@]12C=CC([C@H]3[C@]14C=1C(=C(C=CC1C[C@H]2N(C)CC4)OC)O3)=O Chemical compound OO[C@@]12C=CC([C@H]3[C@]14C=1C(=C(C=CC1C[C@H]2N(C)CC4)OC)O3)=O DXIRRDROGPMTPD-XFKAJCMBSA-N 0.000 description 1
• 239000012425 OXONE® Substances 0.000 description 1
• 239000005642 Oleic acid Substances 0.000 description 1
• ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
• 229940127450 Opioid Agonists Drugs 0.000 description 1
• 229940123257 Opioid receptor antagonist Drugs 0.000 description 1
• DGWFDTKFTGTOAF-UHFFFAOYSA-N P.Cl.Cl.Cl Chemical compound P.Cl.Cl.Cl DGWFDTKFTGTOAF-UHFFFAOYSA-N 0.000 description 1
• 240000001090 Papaver somniferum Species 0.000 description 1
• 235000008753 Papaver somniferum Nutrition 0.000 description 1
• 229920001145 Poly(N-vinylacetamide) Polymers 0.000 description 1
• 229920000954 Polyglycolide Polymers 0.000 description 1
• 239000004372 Polyvinyl alcohol Substances 0.000 description 1
• 239000004260 Potassium ascorbate Substances 0.000 description 1
• IZUBKVGNMPMFKL-KMZXAJPXSA-N S(=O)(=O)(O)O.OC1=CC(OC)=C2C=3[C@@]45[C@@H](O2)C(=O)C=C[C@H]4[C@@H](CC13)N(C)CC5 Chemical compound S(=O)(=O)(O)O.OC1=CC(OC)=C2C=3[C@@]45[C@@H](O2)C(=O)C=C[C@H]4[C@@H](CC13)N(C)CC5 IZUBKVGNMPMFKL-KMZXAJPXSA-N 0.000 description 1
• 101100520662 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) PBA1 gene Proteins 0.000 description 1
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
• CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
• 229930006000 Sucrose Natural products 0.000 description 1
• XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
• BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
• 229930003427 Vitamin E Natural products 0.000 description 1
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
• WCHSQACWYIQTKL-XPWFQUROSA-N [[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2r,3r,4r,5r)-2-(6-aminopurin-9-yl)-4-hydroxy-5-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Chemical compound C1=NC2=C(N)N=CN=C2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1OP(O)(=O)OP(O)(=O)OC[C@H]([C@@H](O)[C@H]1O)O[C@H]1N1C(N=CN=C2N)=C2N=C1 WCHSQACWYIQTKL-XPWFQUROSA-N 0.000 description 1
• TYGDMAQFSSHPRP-UHFFFAOYSA-N acetaldehyde;acetic acid Chemical compound CC=O.CC(O)=O TYGDMAQFSSHPRP-UHFFFAOYSA-N 0.000 description 1
• 229940022663 acetate Drugs 0.000 description 1
• YQNQNVDNTFHQSW-UHFFFAOYSA-N acetic acid [2-[[(5-nitro-2-thiazolyl)amino]-oxomethyl]phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 YQNQNVDNTFHQSW-UHFFFAOYSA-N 0.000 description 1
• VEHZBMGMMPZMRJ-UHFFFAOYSA-N acetic acid;2-(diethylamino)acetic acid Chemical compound CC(O)=O.CCN(CC)CC(O)=O VEHZBMGMMPZMRJ-UHFFFAOYSA-N 0.000 description 1
• PPBFVJQAQFIZNS-UHFFFAOYSA-N acetic acid;ethylcarbamic acid Chemical compound CC(O)=O.CCNC(O)=O PPBFVJQAQFIZNS-UHFFFAOYSA-N 0.000 description 1
• OKTJLQBMTBEEJV-UHFFFAOYSA-N acetic acid;methylcarbamic acid Chemical compound CC(O)=O.CNC(O)=O OKTJLQBMTBEEJV-UHFFFAOYSA-N 0.000 description 1
• 150000008065 acid anhydrides Chemical class 0.000 description 1
• 239000012445 acidic reagent Substances 0.000 description 1
• 229920006243 acrylic copolymer Polymers 0.000 description 1
• 239000012190 activator Substances 0.000 description 1
• 239000004480 active ingredient Substances 0.000 description 1
• 238000005054 agglomeration Methods 0.000 description 1
• 230000002776 aggregation Effects 0.000 description 1
• 239000000556 agonist Substances 0.000 description 1
• 229940072056 alginate Drugs 0.000 description 1
• 235000010443 alginic acid Nutrition 0.000 description 1
• 229920000615 alginic acid Polymers 0.000 description 1
• 150000001335 aliphatic alkanes Chemical class 0.000 description 1
• 125000001931 aliphatic group Chemical group 0.000 description 1
• 150000001340 alkali metals Chemical class 0.000 description 1
• 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
• 229930013930 alkaloid Natural products 0.000 description 1
• 150000003797 alkaloid derivatives Chemical class 0.000 description 1
• 229940087168 alpha tocopherol Drugs 0.000 description 1
• LHTAJTFGGUDLRH-FHHXKLHRSA-N alpha-oxycodol Chemical compound O[C@H]([C@@H]1O2)CC[C@@]3(O)C4([H])N(C)CC[C@]13C1=C2C(OC)=CC=C1C4 LHTAJTFGGUDLRH-FHHXKLHRSA-N 0.000 description 1
• 229910052782 aluminium Inorganic materials 0.000 description 1
• XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
• 125000004103 aminoalkyl group Chemical group 0.000 description 1
• QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
• 230000036592 analgesia Effects 0.000 description 1
• 229940035676 analgesics Drugs 0.000 description 1
• 150000008064 anhydrides Chemical class 0.000 description 1
• 238000005349 anion exchange Methods 0.000 description 1
• 239000000730 antalgic agent Substances 0.000 description 1
• 230000003078 antioxidant effect Effects 0.000 description 1
• 238000013459 approach Methods 0.000 description 1
• 239000012736 aqueous medium Substances 0.000 description 1
• 239000003125 aqueous solvent Substances 0.000 description 1
• 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
• 239000003849 aromatic solvent Substances 0.000 description 1
• 235000010323 ascorbic acid Nutrition 0.000 description 1
• 239000011668 ascorbic acid Substances 0.000 description 1
• 229960005070 ascorbic acid Drugs 0.000 description 1
• 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
• 239000012298 atmosphere Substances 0.000 description 1
• 239000012752 auxiliary agent Substances 0.000 description 1
• 230000001580 bacterial effect Effects 0.000 description 1
• HNYOPLTXPVRDBG-UHFFFAOYSA-M barbiturate Chemical compound O=C1CC(=O)[N-]C(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-M 0.000 description 1
• 229940125717 barbiturate Drugs 0.000 description 1
• 238000010923 batch production Methods 0.000 description 1
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
• 235000019445 benzyl alcohol Nutrition 0.000 description 1
• 150000003938 benzyl alcohols Chemical class 0.000 description 1
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
• WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
• 239000003833 bile salt Substances 0.000 description 1
• 238000010352 biotechnological method Methods 0.000 description 1
• 239000001045 blue dye Substances 0.000 description 1
• 238000009835 boiling Methods 0.000 description 1
• 239000006189 buccal tablet Substances 0.000 description 1
• 239000000872 buffer Substances 0.000 description 1
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
• 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
• 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
• 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
• 239000011575 calcium Substances 0.000 description 1
• 239000008116 calcium stearate Substances 0.000 description 1
• 235000013539 calcium stearate Nutrition 0.000 description 1
• 150000001721 carbon Chemical group 0.000 description 1
• 239000006229 carbon black Substances 0.000 description 1
• 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
• 125000005587 carbonate group Chemical group 0.000 description 1
• BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
• 125000004181 carboxyalkyl group Chemical group 0.000 description 1
• 238000004113 cell culture Methods 0.000 description 1
• 238000005119 centrifugation Methods 0.000 description 1
• 229960000541 cetyl alcohol Drugs 0.000 description 1
• 239000002738 chelating agent Substances 0.000 description 1
• 150000001805 chlorine compounds Chemical class 0.000 description 1
• 238000013375 chromatographic separation Methods 0.000 description 1
• 229910000423 chromium oxide Inorganic materials 0.000 description 1
• 229940001468 citrate Drugs 0.000 description 1
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
• 239000007931 coated granule Substances 0.000 description 1
• 239000008199 coating composition Substances 0.000 description 1
• 230000000052 comparative effect Effects 0.000 description 1
• 239000012141 concentrate Substances 0.000 description 1
• 238000010924 continuous production Methods 0.000 description 1
• 239000008120 corn starch Substances 0.000 description 1
• 238000012937 correction Methods 0.000 description 1
• 229920006037 cross link polymer Polymers 0.000 description 1
• 238000005520 cutting process Methods 0.000 description 1
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
• 230000003247 decreasing effect Effects 0.000 description 1
• 235000019961 diglycerides of fatty acid Nutrition 0.000 description 1
• 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
• VDCSGNNYCFPWFK-UHFFFAOYSA-N diphenylsilane Chemical compound C=1C=CC=CC=1[SiH2]C1=CC=CC=C1 VDCSGNNYCFPWFK-UHFFFAOYSA-N 0.000 description 1
• 239000007884 disintegrant Substances 0.000 description 1
• 239000012738 dissolution medium Substances 0.000 description 1
• LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 1
• 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
• 239000013583 drug formulation Substances 0.000 description 1
• 229940088679 drug related substance Drugs 0.000 description 1
• 238000001035 drying Methods 0.000 description 1
• 239000003995 emulsifying agent Substances 0.000 description 1
• 238000005538 encapsulation Methods 0.000 description 1
• 239000003623 enhancer Substances 0.000 description 1
• 238000003912 environmental pollution Methods 0.000 description 1
• 230000003628 erosive effect Effects 0.000 description 1
• GLVVKKSPKXTQRB-UHFFFAOYSA-N ethenyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC=C GLVVKKSPKXTQRB-UHFFFAOYSA-N 0.000 description 1
• AFSIMBWBBOJPJG-UHFFFAOYSA-N ethenyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC=C AFSIMBWBBOJPJG-UHFFFAOYSA-N 0.000 description 1
• BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
• 125000001033 ether group Chemical group 0.000 description 1
• MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
• 238000002474 experimental method Methods 0.000 description 1
• 239000003925 fat Substances 0.000 description 1
• 239000000835 fiber Substances 0.000 description 1
• 239000007888 film coating Substances 0.000 description 1
• 238000009501 film coating Methods 0.000 description 1
• XUCNUKMRBVNAPB-UHFFFAOYSA-N fluoroethene Chemical compound FC=C XUCNUKMRBVNAPB-UHFFFAOYSA-N 0.000 description 1
• 235000013305 food Nutrition 0.000 description 1
• 230000037406 food intake Effects 0.000 description 1
• 238000004108 freeze drying Methods 0.000 description 1
• WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
• 239000007789 gas Substances 0.000 description 1
• 231100000025 genetic toxicology Toxicity 0.000 description 1
• 230000001738 genotoxic effect Effects 0.000 description 1
• 230000009477 glass transition Effects 0.000 description 1
• 239000008103 glucose Substances 0.000 description 1
• 235000001727 glucose Nutrition 0.000 description 1
• 150000004676 glycans Chemical class 0.000 description 1
• 125000005456 glyceride group Chemical group 0.000 description 1
• 125000005908 glyceryl ester group Chemical group 0.000 description 1
• 238000005469 granulation Methods 0.000 description 1
• 230000003179 granulation Effects 0.000 description 1
• 239000000852 hydrogen donor Substances 0.000 description 1
• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
• 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
• 230000002706 hydrostatic effect Effects 0.000 description 1
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
• 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
• 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
• 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
• 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
• 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
• 229940097275 indigo Drugs 0.000 description 1
• COHYTHOBJLSHDF-UHFFFAOYSA-N indigo powder Natural products N1C2=CC=CC=C2C(=O)C1=C1C(=O)C2=CC=CC=C2N1 COHYTHOBJLSHDF-UHFFFAOYSA-N 0.000 description 1
• 239000003701 inert diluent Substances 0.000 description 1
• 238000002347 injection Methods 0.000 description 1
• 239000007924 injection Substances 0.000 description 1
• 229910001412 inorganic anion Inorganic materials 0.000 description 1
• 150000007529 inorganic bases Chemical class 0.000 description 1
• 229910052500 inorganic mineral Inorganic materials 0.000 description 1
• 239000013067 intermediate product Substances 0.000 description 1
• JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 description 1
• 239000001034 iron oxide pigment Substances 0.000 description 1
• LDHBWEYLDHLIBQ-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide;hydrate Chemical compound O.[OH-].[O-2].[Fe+3] LDHBWEYLDHLIBQ-UHFFFAOYSA-M 0.000 description 1
• JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
• 230000002427 irreversible effect Effects 0.000 description 1
• QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
• 239000012633 leachable Substances 0.000 description 1
• 150000007527 lewis bases Chemical class 0.000 description 1
• 230000000670 limiting effect Effects 0.000 description 1
• 239000012669 liquid formulation Substances 0.000 description 1
• 239000007791 liquid phase Substances 0.000 description 1
• 229910001386 lithium phosphate Inorganic materials 0.000 description 1
• 230000007774 longterm Effects 0.000 description 1
• 230000001050 lubricating effect Effects 0.000 description 1
• 239000011777 magnesium Substances 0.000 description 1
• 229910052749 magnesium Inorganic materials 0.000 description 1
• 229940063002 magnesium palmitate Drugs 0.000 description 1
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
• 235000019341 magnesium sulphate Nutrition 0.000 description 1
• ABSWXCXMXIZDSN-UHFFFAOYSA-L magnesium;hexadecanoate Chemical compound [Mg+2].CCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCC([O-])=O ABSWXCXMXIZDSN-UHFFFAOYSA-L 0.000 description 1
• 229940035034 maltodextrin Drugs 0.000 description 1
• 229940126601 medicinal product Drugs 0.000 description 1
• 150000002734 metacrylic acid derivatives Chemical class 0.000 description 1
• DCUFMVPCXCSVNP-UHFFFAOYSA-N methacrylic anhydride Chemical compound CC(=C)C(=O)OC(=O)C(C)=C DCUFMVPCXCSVNP-UHFFFAOYSA-N 0.000 description 1
• UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
• AXLHVTKGDPVANO-UHFFFAOYSA-N methyl 2-amino-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound COC(=O)C(N)CNC(=O)OC(C)(C)C AXLHVTKGDPVANO-UHFFFAOYSA-N 0.000 description 1
• 229960002921 methylnaltrexone Drugs 0.000 description 1
• 239000003094 microcapsule Substances 0.000 description 1
• 239000011859 microparticle Substances 0.000 description 1
• 239000004005 microsphere Substances 0.000 description 1
• 235000010755 mineral Nutrition 0.000 description 1
• 239000002480 mineral oil Substances 0.000 description 1
• 150000007522 mineralic acids Chemical class 0.000 description 1
• 238000012986 modification Methods 0.000 description 1
• 230000004048 modification Effects 0.000 description 1
• 235000019960 monoglycerides of fatty acid Nutrition 0.000 description 1
• LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 description 1
• 210000004400 mucous membrane Anatomy 0.000 description 1
• 229940043348 myristyl alcohol Drugs 0.000 description 1
• YNTOKMNHRPSGFU-UHFFFAOYSA-N n-Propyl carbamate Chemical compound CCCOC(N)=O YNTOKMNHRPSGFU-UHFFFAOYSA-N 0.000 description 1
• 229940124305 n-propanol Drugs 0.000 description 1
• 229960005297 nalmefene Drugs 0.000 description 1
• 229960005250 naloxone hydrochloride Drugs 0.000 description 1
• DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
• 229960003086 naltrexone Drugs 0.000 description 1
• 239000003887 narcotic antagonist Substances 0.000 description 1
• 238000006386 neutralization reaction Methods 0.000 description 1
• 231100000344 non-irritating Toxicity 0.000 description 1
• 229960002446 octanoic acid Drugs 0.000 description 1
• 239000003921 oil Substances 0.000 description 1
• 235000019198 oils Nutrition 0.000 description 1
• ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
• 229960002969 oleic acid Drugs 0.000 description 1
• 239000003605 opacifier Substances 0.000 description 1
• 239000003401 opiate antagonist Substances 0.000 description 1
• 239000007935 oral tablet Substances 0.000 description 1
• 229940096978 oral tablet Drugs 0.000 description 1
• 150000007530 organic bases Chemical class 0.000 description 1
• 239000003960 organic solvent Substances 0.000 description 1
• 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 239000012188 paraffin wax Substances 0.000 description 1
• 239000004031 partial agonist Substances 0.000 description 1
• 230000036961 partial effect Effects 0.000 description 1
• PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
• 239000002304 perfume Substances 0.000 description 1
• 125000000864 peroxy group Chemical group O(O*)* 0.000 description 1
• 239000000825 pharmaceutical preparation Substances 0.000 description 1
• 239000012071 phase Substances 0.000 description 1
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
• 239000010452 phosphate Substances 0.000 description 1
• 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
• 239000006187 pill Substances 0.000 description 1
• 238000005498 polishing Methods 0.000 description 1
• 229920000747 poly(lactic acid) Polymers 0.000 description 1
• 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
• 229920002401 polyacrylamide Polymers 0.000 description 1
• 229920000447 polyanionic polymer Polymers 0.000 description 1
• 239000004417 polycarbonate Substances 0.000 description 1
• 229920000515 polycarbonate Polymers 0.000 description 1
• 229920000728 polyester Polymers 0.000 description 1
• 239000004633 polyglycolic acid Substances 0.000 description 1
• 239000004626 polylactic acid Substances 0.000 description 1
• 229920001282 polysaccharide Polymers 0.000 description 1
• 239000005017 polysaccharide Substances 0.000 description 1
• 229920002635 polyurethane Polymers 0.000 description 1
• 239000004814 polyurethane Substances 0.000 description 1
• 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
• 229920002451 polyvinyl alcohol Polymers 0.000 description 1
• 235000019275 potassium ascorbate Nutrition 0.000 description 1
• 229940017794 potassium ascorbate Drugs 0.000 description 1
• 239000001103 potassium chloride Substances 0.000 description 1
• 235000011164 potassium chloride Nutrition 0.000 description 1
• 229940096992 potassium oleate Drugs 0.000 description 1
• 239000012286 potassium permanganate Substances 0.000 description 1
• OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
• 229910000160 potassium phosphate Inorganic materials 0.000 description 1
• 235000011009 potassium phosphates Nutrition 0.000 description 1
• 235000010241 potassium sorbate Nutrition 0.000 description 1
• 239000004302 potassium sorbate Substances 0.000 description 1
• 229940069338 potassium sorbate Drugs 0.000 description 1
• OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
• 229910052939 potassium sulfate Inorganic materials 0.000 description 1
• 235000011151 potassium sulphates Nutrition 0.000 description 1
• CONVKSGEGAVTMB-RXSVEWSESA-M potassium-L-ascorbate Chemical compound [K+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] CONVKSGEGAVTMB-RXSVEWSESA-M 0.000 description 1
• MLICVSDCCDDWMD-KVVVOXFISA-M potassium;(z)-octadec-9-enoate Chemical compound [K+].CCCCCCCC\C=C/CCCCCCCC([O-])=O MLICVSDCCDDWMD-KVVVOXFISA-M 0.000 description 1
• 239000003755 preservative agent Substances 0.000 description 1
• 238000003825 pressing Methods 0.000 description 1
• 230000002265 prevention Effects 0.000 description 1
• 230000002035 prolonged effect Effects 0.000 description 1
• XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
• 239000000473 propyl gallate Substances 0.000 description 1
• 235000010388 propyl gallate Nutrition 0.000 description 1
• 229940075579 propyl gallate Drugs 0.000 description 1
• 125000006239 protecting group Chemical group 0.000 description 1
• 230000001681 protective effect Effects 0.000 description 1
• 230000000541 pulsatile effect Effects 0.000 description 1
• 238000011084 recovery Methods 0.000 description 1
• 239000001044 red dye Substances 0.000 description 1
• 230000000979 retarding effect Effects 0.000 description 1
• YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
• 229960001860 salicylate Drugs 0.000 description 1
• 229920006395 saturated elastomer Polymers 0.000 description 1
• 238000000926 separation method Methods 0.000 description 1
• 238000007493 shaping process Methods 0.000 description 1
• RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
• 235000012239 silicon dioxide Nutrition 0.000 description 1
• 239000002002 slurry Substances 0.000 description 1
• WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
• 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
• 229940100996 sodium bisulfate Drugs 0.000 description 1
• 229910000033 sodium borohydride Inorganic materials 0.000 description 1
• 239000012279 sodium borohydride Substances 0.000 description 1
• 239000011780 sodium chloride Substances 0.000 description 1
• CSMWJXBSXGUPGY-UHFFFAOYSA-L sodium dithionate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 description 1
• JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
• 229910001379 sodium hypophosphite Inorganic materials 0.000 description 1
• RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
• 239000001488 sodium phosphate Substances 0.000 description 1
• 229910000162 sodium phosphate Inorganic materials 0.000 description 1
• 235000011008 sodium phosphates Nutrition 0.000 description 1
• 229940006186 sodium polystyrene sulfonate Drugs 0.000 description 1
• 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
• 229910052938 sodium sulfate Inorganic materials 0.000 description 1
• 235000011152 sodium sulphate Nutrition 0.000 description 1
• 239000011949 solid catalyst Substances 0.000 description 1
• 239000007790 solid phase Substances 0.000 description 1
• 239000002195 soluble material Substances 0.000 description 1
• 235000010199 sorbic acid Nutrition 0.000 description 1
• 239000004334 sorbic acid Substances 0.000 description 1
• 229940075582 sorbic acid Drugs 0.000 description 1
• 239000000600 sorbitol Substances 0.000 description 1
• 238000005563 spheronization Methods 0.000 description 1
• 239000007921 spray Substances 0.000 description 1
• 238000001694 spray drying Methods 0.000 description 1
• 239000003381 stabilizer Substances 0.000 description 1
• 238000010561 standard procedure Methods 0.000 description 1
• 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 238000003860 storage Methods 0.000 description 1
• 239000010902 straw Substances 0.000 description 1
• 239000005720 sucrose Substances 0.000 description 1
• YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
• 239000004094 surface-active agent Substances 0.000 description 1
• 229940095064 tartrate Drugs 0.000 description 1
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• 230000001225 therapeutic effect Effects 0.000 description 1
• 229960000984 tocofersolan Drugs 0.000 description 1
• 238000000844 transformation Methods 0.000 description 1
• TWQULNDIKKJZPH-UHFFFAOYSA-K trilithium;phosphate Chemical compound [Li+].[Li+].[Li+].[O-]P([O-])([O-])=O TWQULNDIKKJZPH-UHFFFAOYSA-K 0.000 description 1
• RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
• 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
• 238000005292 vacuum distillation Methods 0.000 description 1
• 229940070710 valerate Drugs 0.000 description 1
• NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
• 239000003981 vehicle Substances 0.000 description 1
• 235000019165 vitamin E Nutrition 0.000 description 1
• 229940046009 vitamin E Drugs 0.000 description 1
• 239000011709 vitamin E Substances 0.000 description 1
• 229920003176 water-insoluble polymer Polymers 0.000 description 1
• 230000004584 weight gain Effects 0.000 description 1
• 235000019786 weight gain Nutrition 0.000 description 1
• 238000005550 wet granulation Methods 0.000 description 1
• 239000000080 wetting agent Substances 0.000 description 1
• 235000014101 wine Nutrition 0.000 description 1
• 229910052725 zinc Inorganic materials 0.000 description 1
• 239000011701 zinc Substances 0.000 description 1
• 239000002076 α-tocopherol Substances 0.000 description 1
• 235000004835 α-tocopherol Nutrition 0.000 description 1